Aggresomes predict poor outcomes and implicate proteostasis in the pathogenesis of pediatric choroid plexus tumors

Amer, Nada; Taha, Hala; Hesham, Dina; Al-Shehaby, Nouran; Mosaab, Amal; Soudy, Mohamed; Osama, Aya; Mahmoud, Noura; El‐Ayadi, Moatasem; Youssef, Ayda; El-Beltagy, Mohamed; Zaghloul, Mohamed S.; Magdeldin, Sameh; Sayed, Ahmed; El‐Naggar, Shahenda

doi:10.1007/s11060-020-03694-3

Cited by 8 publications

(3 citation statements)

References 57 publications

(77 reference statements)

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“…The involvement of PSMD9 in the regulation of protein translation, aggregation, and degradation via the proteasome, through protein-protein interaction, and presence of specific domain-motifs makes PSMD9 a crucial regulatory protein in protein homeostasis. Enhanced protein translation, formation of aggresomes, and lipid droplets, as well as suppression of the UPR are characteristics of many diseases, including cancer [62], neurological disorders [63], and aging [64]. PSMD9 is associated with the disease pathology of diabetes [12], neurological disorders such as depression [65], anxiety [66], schizophrenia [67], and cancer [13,14].…”

Section: Discussionmentioning

confidence: 99%

The interaction network of the proteasome assembly chaperone PSMD9 regulates proteostasis

Christie,

Anthony,

Harish

et al. 2023

The FEBS Journal

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Functional networks in cells are created by physical, genetic, and regulatory interactions. Mapping them and annotating their functions by available methods remains a challenge. We use affinity purification mass spectrometry (AP‐MS) coupled with SLiMFinder to discern such a network involving 26S proteasome non‐ATPase regulatory subunit 9 (PSMD9), a chaperone of proteasome assembly. Approximately 20% of proteins within the PSMD9 interactome carry a short linear motif (SLiM) of the type ‘EXKK’. The binding of purified PSMD9 with the peptide sequence ERKK, proteins heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNPA2B1; containing ERKK), and peroxiredoxin‐6 (PRDX6; containing EAKK) provided proof of principle for this motif‐driven network. The EXKK motif in the peptide primarily interacts with the coiled‐coil N domain of PSMD9, a unique interaction not reported for any coiled‐coil domain. PSMD9 knockout (KO) HEK293 cells experience endoplasmic reticulum (ER) stress and respond by increasing the unfolded protein response (UPR) and reducing the formation of aggresomes and lipid droplets. Trans‐expression of PSMD9 in the KO cells rescues lipid droplet formation. Overexpression of PSMD9 in HEK293 cells results in reduced UPR, and increased lipid droplet and aggresome formation. The outcome argues for the prominent role of PSMD9 in maintaining proteostasis. Probable mechanisms involve the binding of PSMD9 to binding immunoglobulin protein (BIP/GRP78; containing EDKK), an endoplasmic reticulum chaperone and key regulator of the UPR, and fatty acid synthase (FASN; containing ELKK), involved in fatty acid synthesis/lipid biogenesis. We propose that PSMD9 acts as a buffer in the cellular milieu by moderating the UPR and enhancing aggresome formation to reduce stress‐induced proteotoxicity. Akin to waves created in ponds that perpetuate to a distance, perturbing the levels of PSMD9 would cause ripples down the networks, affecting final reactions in the pathway, one of which is altered proteostasis.

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Section: Discussionmentioning

confidence: 99%

The interaction network of the proteasome assembly chaperone PSMD9 regulates proteostasis

Christie,

Anthony,

Harish

et al. 2023

The FEBS Journal

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“…Furthermore, considering that (i) YTHDF2 plays a protective role in cell survival by promoting aggresome formation (Fig. 5 ), (ii) aggresomes predict poor outcomes in the pathogenesis of several cancers 63 , 64 , and (iii) YTHDF2 is very closely associated with cancer progression 65 , 66 , a role of YTHDF2 as an aggresome-targeting factor as well as m 6 A reader needs more comprehensive investigation in the future.…”

Section: Discussionmentioning

confidence: 99%

YTHDF2 facilitates aggresome formation via UPF1 in an m6A-independent manner

Hwang,

Park,

Kim

et al. 2023

Nat Commun

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YTHDF2 has been extensively studied and typified as an RNA-binding protein that specifically recognizes and destabilizes RNAs harboring N6-methyladenosine (m6A), the most prevalent internal modification found in eukaryotic RNAs. In this study, we unravel the m6A-independent role of YTHDF2 in the formation of an aggresome, where cytoplasmic protein aggregates are selectively sequestered upon failure of protein homeostasis mediated by the ubiquitin-proteasome system. Downregulation of YTHDF2 in HeLa cells reduces the circularity of aggresomes and the rate of movement of misfolded polypeptides, inhibits aggresome formation, and thereby promotes cellular apoptosis. Mechanistically, YTHDF2 is recruited to a misfolded polypeptide-associated complex composed of UPF1, CTIF, eEF1A1, and DCTN1 through its interaction with UPF1. Subsequently, YTHDF2 increases the interaction between the dynein motor protein and the misfolded polypeptide-associated complex, facilitating the diffusion dynamics of the movement of misfolded polypeptides toward aggresomes. Therefore, our data reveal that YTHDF2 is a cellular factor involved in protein quality control.

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“…Tumors of the CP comprise ~20% of brain tumors diagnosed in children under 1 year of age [ 6 , 7 ]. Research aimed at understanding the origin and molecular characteristics of CP carcinoma (CPC) is essential for developing new therapies to improve clinical outcomes [ 8 – 12 ].…”

Section: Introductionmentioning

confidence: 99%

Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development

Han

Singh

et al. 2022

Cell Death Differ

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Multiciliated cells (MCCs) in the brain reside in the ependyma and the choroid plexus (CP) epithelia. The CP secretes cerebrospinal fluid that circulates within the ventricular system, driven by ependymal cilia movement. Tumors of the CP are rare primary brain neoplasms mostly found in children. CP tumors exist in three forms: CP papilloma (CPP), atypical CPP, and CP carcinoma (CPC). Though CPP and atypical CPP are generally benign and can be resolved by surgery, CPC is a particularly aggressive and little understood cancer with a poor survival rate and a tendency for recurrence and metastasis. In contrast to MCCs in the CP epithelia, CPCs in humans are characterized by solitary cilia, frequent TP53 mutations, and disturbances to multiciliogenesis program directed by the GMNC-MCIDAS transcriptional network. GMNC and MCIDAS are early transcriptional regulators of MCC fate differentiation in diverse tissues. Consistently, components of the GMNC-MCIDAS transcriptional program are expressed during CP development and required for multiciliation in the CP, while CPC driven by deletion of Trp53 and Rb1 in mice exhibits multiciliation defects consequent to deficiencies in the GMNC-MCIDAS program. Previous studies revealed that abnormal NOTCH pathway activation leads to CPP. Here we show that combined defects in NOTCH and Sonic Hedgehog signaling in mice generates tumors that are similar to CPC in humans. NOTCH-driven CP tumors are monociliated, and disruption of the NOTCH complex restores multiciliation and decreases tumor growth. NOTCH suppresses multiciliation in tumor cells by inhibiting the expression of GMNC and MCIDAS, while Gmnc-Mcidas overexpression rescues multiciliation defects and suppresses tumor cell proliferation. Taken together, these findings indicate that reactivation of the GMNC-MCIDAS multiciliogenesis program is critical for inhibiting tumorigenesis in the CP, and it may have therapeutic implications for the treatment of CPC.

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Aggresomes predict poor outcomes and implicate proteostasis in the pathogenesis of pediatric choroid plexus tumors

Cited by 8 publications

References 57 publications

The interaction network of the proteasome assembly chaperone PSMD9 regulates proteostasis

The interaction network of the proteasome assembly chaperone PSMD9 regulates proteostasis

YTHDF2 facilitates aggresome formation via UPF1 in an m6A-independent manner

Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development

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